Improving delivery of molecularly targeted agents to glioma.

Abstract

Treatment of glioblastoma multiforme is at a crossroads. Promising new molecularly-targeted agents have failed to show any significant clinical benefit. Treatment is particularly challenging since the tumor resides in a tissue that is considered to be a pharmacological and immunological sanctuary due to the presence of the blood-brain barrier. Protective mechanisms at the blood-brain barrier (BBB), such as the endothelial tight junctions and drug efflux transporters, restrict the passage of most large and small molecules into the brain. Limited drug delivery to the tumor is a plausible explanation for the failure of molecularly-targeted therapy in glioma. If therapeutic agents do not reach their target, regardless of their potency, they cannot be effective. The objective of this work was to show that active efflux transporters at BBB restrict delivery of potent molecularly-targeted agents to their targets. More importantly, the aim was to demonstrate that the targets in question are in invasive tumor cells that are left behind after surgery and remain shielded behind an intact blood-brain barrier. The ultimate goal of this endeavor is to improve delivery of molecularly-targeted therapy to the tumor and show that this can translate to enhanced efficacy against this lethal disease. We show that brain distribution of the tyrosine kinase inhibitors, gefitinib, erlotinib and sorafenib, is restricted due to active efflux mediated by p-glycoprotein (P-gp) and the breast cancer resistance protein (BCRP). We further demonstrate that delivery of these drugs to the brain increases dramatically when the two transporters are genetically absent or pharmacologically inhibited. Using a rat xenograft model and a spontaneous mouse model of glioma, we show that the BBB is heterogeneously disrupted in the brain. The blood-brain barrier is disrupted in the tumor core resulting in high tumoral concentrations of erlotinib and dasatinib. However, it is intact in areas immediately adjacent to the tumor, and therefore restricts drug delivery to these sites. Thus, clinical assessment of drug delivery when using drug concentrations in tumor core (the resected tissue) as a guide for the adequacy of drug delivery can be misleading. Furthermore, we show that increasing drug delivery to these areas, by genetic deletion or pharmacological inhibition of P-gp and BCRP, results in a remarkable enhancement in efficacy of the tyrosine kinase inhibitor, dasatinib. Finally, we show that efficacy of dasatinib increases dramatically in tumor bearing transgenic mice, that are deficient in P-gp and BCRP, and consequently, these mice survive for a significantly longer time compared to the wild-type mice. These observations underline that restricted delivery of molecularly-targeted agents to their targets can be a significant determinant of drug efficacy against glioma. In an invasive tumor, such as glioblastoma, it is important to realize that the target resides within the invasive glioma cells, that remain shielded by an intact blood-brain barrier, and evade chemotherapy. Overall, this work highlights the need to develop strategies to improve drug delivery to the invasive tumor in glioma and translate these strategies to the clinic.